Addition reactions of ketones

The mechanistic pattern established by study of hydration and alcohol addition reactions of ketones and aldehydes is followed in a number of other reactions of carbonyl compounds. Reactions at carbonyl centers usually involve a series of addition and elimination steps proceeding through tetrahedral intermediates. These steps can be either acid-catalyzed or base-catalyzed. The rate and products of the reaction are determined by the reactivity of these tetrahedral intermediates. 

The first element of stereocontrol in aldol addition reactions of ketone enolates is the enolate structure. Most enolates can exist as two stereoisomers. In Section 1.1.2, we discussed the factors that influence enolate composition. The enolate formed from 2,2-dimethyl-3-pentanone under kinetically controlled conditions is the Z-isomer.5 When it reacts with benzaldehyde only the syn aldol is formed.4 The product stereochemistry is correctly predicted if the TS has a conformation with the phenyl substituent in an equatorial position. 

Carbolithiation reactions of ketone a,-dianions, generated by the above amine-free method with several alkenes, such as styrenyl derivatives, vinyl sulfides and vinylsilanes, can lead to the generation of ketone a,5-dianions (Scheme 15)14. For example, when one equivalents of triphenylvinylsilane was treated with a ketone a,-dianion, in THF, at 0 C for 1 h and the resulting reaction mixture was quenched by 2.2 mol equivalents of trimethylchlorosilane, the corresponding bis-silylated enol silyl ether was obtained. Substituted styrenyl derivatives, such as 1,1-diphenylethylene and cinnamyl alcohol, also underwent a smooth carbolithiation to give the corresponding ketone a,5-dianions. Similar addition reactions of ketone a,f)-dianions to vinyl phenyl sulfide took place smoothly to give a,5-dianions with a sulfur attached in the 5-position. 

Nucleophilic Addition Reactions of Ketones and Aldehydes (Chapter 19)... 

Aldol addition reactions of ketones are rarely successful, since they are usually endoergonic. For example, the base-mediated aldolization of acetone provides only a few percent of the aldol, diacetone alcohol (equation 26). However, the conversion may be accomplished in 75% yield by refluxing acetone under a Soxhlet extractor containing calcium or barium hydroxide. - On the other hand, di-methoxyacetone dimerizes under basic conditions to the aldol, with an equilibrium constant significantly greater than unity (K = 10 dm mol equation 27). The difference in equilibrium constants of equations (26) and (27) parallels the equilibrium constants for hydration of the two ketones, and results from the inductive effect of the methoxy groups. 

The intramolecular Michael addition reaction of ketone enolate to p-alkoxyacrylate proceeded selectively (in a ratio of 5.9 1) with Barton s base (5) to give tetrahydrofuran 36 [8]. In a model smdy, LDA was much less effective than Barton s base (28 5% versus 96% yield). The diester 36 was converted into 38, which corresponds to the A-D ring system for lactonamycin (39) (Scheme 7.6). 

Scheme 12.3 Anti- and q n-aldol addition reactions of ketones with benzaldehyde derivatives.

Scheme 19.71 Secondary amine-thiourea mediated Mannich addition reactions of ketones and aldehydes to preformed or in situ generated imines.

The importance of the dipolar resonance forms is reflected in the stabihties of isomeric carbonyl compounds. Propanal is approximately 27 kj mole" less stable than propanone. For addition reactions, two isomeric products with different stabihties also form. Therefore, we also have to consider the relative stabihties of the products. Hydrogenation of propanal and propanone gives isomeric alcohols. 1-Propanol is approximately 16 kJ mole" less stable than 2-propanol. Since the difference in the stabihties of the reactants is greater than the difference in the stabilities of the products, the equihbrium constants for the addition reactions of carbonyl compounds depend on more differences in the structure of the carbonyl compound than on the differences in the structure of the addition product. Thus, because ketones are more stable than aldehydes, the addition reactions of ketones are less favorable (have smaller equihbrium constants) than addition reactions of aldehydes. 

We have already seen that the carbonyl addition reactions of ketones occur less readily than the addition reactions of aldehydes because ketones are more stable. Steric effects are also important. The two groups bonded to sp -hybridized carbonyl carbon atom in the product are 120° apart. These groups block the approach of the nucleophile. Since a ketone has two alkyl (or aryl) groups, a ketone is more stericaUy hindered than an aldehyde having the same alkyl group. Thus, ketones react more slowly than aldehydes (Figure 19.1)... 

For example, Tang and coworkers found that bifunctional thiourea catalyst 40 could efficiently promote the asymmetric Michael addition reactions of ketones or a-branched aldehydes with various Michael acceptors (Scheme 1.16) [223]. In particular, the driving force in the present system can be ascribed to the strong hydrogen bond-forming character of thiourea with nitroolefrn acceptors, as depicted in the transition state model 46. 

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